Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)

Phase 3

Completed

Conditions: Lupus Erythematosus, Systemic

Interventions: Drug: Placebo atorvastatin
Drug: Atorvastatin

Registration Number: NCT00065806

Lead Sponsor: Laura Schanberg

Brief Summary: The purpose of this study is:

1. To assess the efficacy of a lipid-lowering agent (atorvastatin) on the development of atherosclerosis that predisposes children with SLE to cardiovascular events in adulthood.

2. To assess the safety of intermediate-term (36 months) treatment of children and young adults with atorvastatin.

3. To further characterize the course of SLE in children and young adults, by establishing a cohort of pediatric SLE patients to be followed prospectively.

4. To establish a mechanism for conducting clinical trials in rare pediatric rheumatic diseases using the Children's Arthritis and Rheumatology Research Alliance (CARRA).

Detailed Description: Children and adolescents with SLE represent 15% of all SLE patients. Children with SLE suffer high morbidity that affects many organ systems, reduces their quality of life, and shortens their lifespan. As more children with SLE survive into adulthood, atherosclerotic cardiovascular disease has emerged as a major concern. SLE is a significant risk factor for myocardial infarction and death in young premenopausal women with SLE, even after controlling for traditional cardiovascular risk factors. Acceleration of atherogenesis in SLE most likely reflects SLE-associated vascular immune and inflammatory changes.

Although limited, the data on cardiovascular and lipid abnormalities in children with SLE implicate atherosclerosis as an important cause of long-term morbidity and mortality. The 3-hydroxy-3-methlglutaryl-coenzyme A (HMG CoA) reductase inhibitors, or statins, reduce mortality and morbidity from atherosclerosis in adults and have intrinsic anti-inflammatory and immune modulatory properties. These anti-inflammatory and immune modulatory activities may have particular benefit in the prevention and treatment of atherosclerosis in SLE. This trial will evaluate atorvastatin in children with SLE in the largest cohort of pediatric SLE patients ever studied prospectively.

Children in this study will be randomized to receive either atorvastatin or a placebo. All children will be followed for 3 years, during which they will have 15 study visits. Study visits will generally last 2 hours and will include medical interview, medication review and pill count, physical examination, and blood and urine tests. Cardiovascular-specific outcome measures will include assessments of high sensitivity CRP; fasting lipid profile; homocysteine level; apolipoprotein A, B1, and Lp(a); carotid intima media thickness (IMT); and tensor diffusion/MRI.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 221

Inclusion Criteria

Meets American College of Rheumatology (ACR) revised diagnostic guidelines for SLE
Weight of 25 kg (55 lbs) or more
Outpatient
Ability to complete self-report questionnaires in either English or Spanish
Willingness to comply with recommended diet
Acceptable methods of contraception

Exclusion Criteria

Drug-induced lupus
Liver disease (ALT or aspartate aminotransferase greater than 2 X normal value)
Myositis (CK greater than 3 X normal value)
Inability to obtain adequate-quality IMT images
Current use of oral or parenteral tacrolimus or cyclosporine
Dialysis or serum creatinine reater than 2.5 mg/dL
Active nephrotic syndrome (urinary protein greater than 3 g/24 h and serum albumin less than 2.3 g/dl)
Total cholesterol greater than 350 mg/dL
Xanthoma
Familial hypercholesterolemia
Pregnant or breastfeeding
Use of estrogen-containing contraceptives (e.g., Lo-Ovral)
Unable to adhere to study regimen
Life-threatening non-SLE illness that would interfere with ability to complete the study
Current drug or alcohol abuse
Anticipated poor compliance
Participation in another drug intervention study within 30 days of study enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Placebo atorvastatin	Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes \[TLC\] diet, \[http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi\]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus placebo at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd placebo for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.
1	Atorvastatin	Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes \[TLC\] diet, \[http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi\]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus atorvastatin at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd atorvastatin for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.

Primary Outcome Measures

Name	Time	Method
Change in Mean-Mean Common Carotid IMT (CIMT)	Change from baseline to 36 months	For the common carotid arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right common near wall mean, right common far wall mean, left common near wall mean and left common far wall mean). These summary variables were then averaged to estimate a single mean-mean common CIMT for each participant visit.

Secondary Outcome Measures

Name	Time	Method
Change in LDL Cholesterol	Change from baseline to 36 months
Change in Triglycerides	Change from baseline to 36 months
Change in Lipoprotein A	Change from baseline to 36 months
Change in Homocysteine	Change from baseline to 36 months
Change in Total Cholesterol	Change from baseline to 36 months
Change in HDL Cholesterol	Change from baseline to 36 months
Change in Mean-Max CIMT	Change from baseline to 36 months	For each side, segment and wall, the maximum CIMT over the 4 angles of interrogation was selected to produce 12 summary variables (right common near wall max, right common far wall max, right bifurcation near wall max, right bifurcation far wall max, right internal near wall max, right internal far wall max, left common near wall max, left common far wall max, left bifurcation near wall max, left bifurcation far wall max, left internal near wall max and left internal far wall max). These 12 summary variables were then averaged to estimate a single mean-max CIMT for each participant visit.
Change in Mean-Mean CIMT	Change from baseline to 36 months	For each side, segment and wall, mean CIMT values were averaged over the 4 angles of interrogation to produce 12 summary variables (right common near wall mean, right common far wall mean, right bifurcation near wall mean, right bifurcation far wall mean, right internal near wall mean, right internal far wall mean, left common near wall mean, left common far wall mean, left bifurcation near wall mean, left bifurcation far wall mean, left internal near wall mean and left internal far wall mean). These 12 summary variables were then averaged to estimate a single mean-mean CIMT for each participant visit.
Change in Mean-Max Common CIMT	Change from baseline to 36 months	For each side and wall of the common carotid arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right common near wall max, right common far wall max, left common near wall max and left common far wall max). These summary variables were then averaged to estimate a single mean-max common CIMT for each participant visit.
Change in Mean-Max Internal CIMT	Change from baseline to 36 months	For each side and wall of the internal carotid arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right internal near wall max, right internal far wall max, left internal near wall max and left internal far wall max). These summary variables were then averaged to estimate a single mean-max internal CIMT for each participant visit.
Change in Mean-Mean Internal CIMT	Change from baseline to 36 months	For the internal carotid arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right internal near wall mean, right internal far wall mean, left internal near wall mean and left internal far wall mean). These summary variables were then averaged to estimate a single mean-mean internal CIMT for each participant visit.
Change in Mean-Max Bifurcation CIMT	Change from baseline to 36 months	For each side and wall of the bifurcation arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right bifurcation near wall max, right bifurcation far wall max, left bifurcation near wall max and left bifurcation far wall max). These summary variables were then averaged to estimate a single mean-max bifurcation CIMT for each participant visit.
Change in Mean-Mean Bifurcation CIMT	Change from baseline to 36 months	For the bifurcation arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right bifurcation near wall mean, right bifurcation far wall mean, left bifurcation near wall mean and left bifurcation far wall mean). These summary variables were then averaged to estimate a single mean-mean bifurcation CIMT for each participant visit.
Change in Mean-Max Far Wall CIMT	Change from baseline to 36 months	For the far wall measurements for each side and segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 6 summary variables (right common far wall max, right bifurcation far wall max, right internal far wall max, left common far wall max, left bifurcation far wall max, and left internal far wall max). These 6 summary variables were then averaged to estimate a single mean-max far wall CIMT for each participant visit.
Change in Mean-Mean Far Wall CIMT	Change from baseline to 36 months	For the far wall measurements for each side and segment, mean CIMT values were averaged over the 4 angles of interrogation to produce 6 summary variables (right common far wall mean, right bifurcation far wall mean, right internal far wall mean, left common far wall mean, left bifurcation far wall mean and left internal far wall mean). These 6 summary variables were then averaged to estimate a single mean-mean far wall CIMT for each participant visit.
Change in Mean-Max Near Wall CIMT	Change from baseline to 36 months	For the near wall measurements for each side and segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 6 summary variables (right common near wall max, right bifurcation near wall max, right internal near wall max, left common near wall max, left bifurcation near wall max, and left internal near wall max). These 6 summary variables were then averaged to estimate a single mean-max near wall CIMT for each participant visit.
Change in Mean-Mean Near Wall CIMT	Change from baseline to 36 months	For the near wall measurements for each side and segment, mean CIMT values were averaged over the 4 angles of interrogation to produce 6 summary variables (right common near wall mean, right bifurcation near wall mean, right internal near wall mean, left common near wall mean, left bifurcation wall mean and left internal far wall mean). These 6 summary variables were then averaged to estimate a single mean-mean far wall CIMT for each participant visit.
Change in Natural Log of mg/L for hsCRP	Change from baseline to 36 months